DESCRIPTION: The goal of this application is to explore the molecular basis for the long-term carcinogenic effects associated with chronic exposure to arsenic. Arsenic is representative of a broad class of toxins and carcinogens for which no discernible mutagenesis is detectable. There is, however, a cellular response to arsenic exposure that consists of increased transcription and post-translational product for a variety of cellular genes, some of which are known, and many of which remain unidentified. Understanding the mechanism of this cellular adaptation to chronic arsenic exposure is a primary focus of this application. Toward this goal, proposed experiments focus upon the arsenic-induced expression of one transcription factor, CHOP (C/EBP Homology Protein). Dr. Ron's group has done substantial previous analysis of this factor, and they hypothesize that it plays the role of an early master switch in acting to induce the expression of other, arsenic-induced growth regulators. By so doing, CHOP links, via its target genes, arsenic exposure to changes in cellular replication that may explain how arsenic and similar toxins contribute to cancer formation. Based upon his hypothesis of the central role for CHOP, the investigator develops three aims, which include: 1) to develop mice in which both alleles of the CHOP gene have been knocked out, 2) to define the differences in phenotype between normal and CHOP-deficient mice and isolated cells when they are exposed to toxins like arsenic that are known to induce CHOP, and 3) to isolate and identify members of the battery of genes that are induced by CHOP in response to arsenic. These genes are referred to as CHOP-dependent, arsenic-induced genes. By identifying this battery of genes, he hopes to be able to better explain how chronic arsenic exposure serves to promote cancer development. In summary, the investigator plans to develop CHOP knockout mice, and by so doing, enable a logical series of experiments that will serve to clarify what genes are activated specifically by the CHOP transcription factor following arsenic exposure. By identifying these genes, the investigator hopes to explain how non-mutagenic toxins like arsenic can contribute to cell transformation.